ABSTRACT Burn injury is a major clinical challenge. The causes of burns are vast and diverse, as are the sites of injury. Yet, the overwhelmingly majority of burn victims experience intense spontaneous pain and persistent allodynia, often years after their injury. Opioids are the standard of care for post-burn pain management, but over half of burn victims report inadequate relief, thereby increasing the risk for prolonged, and even irreversible, disability. In addition, opioids clearly exert dangerous side effects that include cognitive dysfunction, respiratory depression, tolerance, and dependence. Accordingly, there is an unquestionable need for research directed at understanding mechanisms of post-burn pain to identify novel targets for development of effective analgesics devoid of unwanted side effects. Burns to the head and neck are the most common sites of injury and amongst the most painful for patients. However, to our knowledge, there are no existing animal models of facial burn injury and this represents a major barrier in solving this severe pain condition. A primary objective of this application is to develop and characterize a rodent model of partial thickness facial burn injury and to employ it to address orofacial mechanisms of persistent post-burn pain. Clinical studies have revealed that administration of lidocaine by a peripheral nerve block to the site of injury produces robust pain relief, indicating that persistent input from sensory afferent terminals is a critical mediator of post-burn pain. However, there is a large gap in knowledge regarding how burn modulates neuronal activity leading to persistent spontaneous pain and modality-specific hypersensitivities beyond complete resolution of the injury itself. Here, we propose to test the central hypothesis that partial thickness facial burn injury induces transcriptional changes that sensitize sensory neurons and contribute to the development of persistent hyperalgesia/allodynia. To test the hypothesis, we will: (1) develop a mouse model of facial burn injury, and (2) identify transcriptional changes in back-labeled trigeminal ganglia neurons that mediate persistent pain after burn injury. This project has substantial health significance as it proposes an innovative combination of complementary methodologies to elucidate peripheral contributions to persistent post-burn pain. These studies will provide a foundation for future investigation into craniofacial burn pain and ultimately aid in the search for an effective treatment. Moreover, these techniques and research methods provide an ideal training vehicle for a career as an academic clinician-scientist.